Antitubercular Drugs
Objectives
When you reach the end of this chapter, you will be able to do the following:
1 Identify the various first-line and second-line drugs indicated for the treatment of tuberculosis.
Drug Profiles
Key Terms
Aerobic Requiring oxygen for the maintenance of life. (p. 673)
Antitubercular drugs Drugs used to treat infections caused by Mycobacterium bacterial species. (p. 674)
Bacillus A rod-shaped bacterium. (p. 673)
Granulomas Small nodular aggregations of inflammatory cells (e.g., macrophages, lymphocytes); usually characterized by clearly delimited boundaries, as found in tuberculosis. (p. 673)
Isoniazid The primary and most commonly prescribed tuberculostatic drug. (p. 674)
Multidrug-resistant tuberculosis (MDR-TB) Tuberculosis that demonstrates resistance to two or more drugs. (p. 673)
Slow acetylator An individual with a genetic defect that causes a deficiency in the enzyme needed to metabolize isoniazid, the most widely used tuberculosis drug. (p. 677)
Tubercle The characteristic lesion of tuberculosis; a small round gray translucent granulomatous lesion, usually with a caseated (cheesy) consistency in its interior. (See granuloma.) (p. 673)
Tubercle bacilli Another common name for rod-shaped tuberculosis bacteria; essentially synonymous with Mycobacterium tuberculosis. (p. 673)
Tuberculosis (TB) Any infectious disease caused by species of Mycobacterium, usually Mycobacterium tuberculosis (adjectives: tuberculous, tubercular). (p. 673)
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Anatomy, Physiology, and Pathophysiology Overview
Pathophysiology of Tuberculosis
Tuberculosis (TB) is the medical diagnosis for any infection caused by a bacterial species known as Mycobacterium. TB is most commonly characterized by granulomas in the lungs. These are nodular accumulations of inflammatory cells (e.g., macrophages, lymphocytes) that are delimited (“walled off” with clear boundaries) and have a center that has a cheesy or caseated consistency. (Casein is the name of a protein that is prevalent in cheese and milk.) Although there are two mycobacterial species that can cause TB, Mycobacterium tuberculosis and Mycobacterium bovis, infections caused by M. tuberculosis (abbreviated MTB) are the most common. There are also several other mycobacterial species, including Mycobacterium leprae, which causes leprosy, and Mycobacterium avium-intracellulare complex, which causes a disease that is similar to TB but often has gastrointestinal symptoms, both of which have varying susceptibility to different drugs used for TB. Infections with these bacteria are much less of a public health problem and hence are not the focus of this chapter.
MTB is an aerobic bacillus, which means that it is a rod-shaped microorganism (bacillus) that requires a large supply of oxygen to grow and flourish (aerobic). This bacterium’s need for a highly oxygenated body site explains why Mycobacterium infections most commonly affect the lungs. Other common sites of infection are the growing ends of bones and the brain (cerebral cortex). Less common sites of infection include the kidney, liver, and genitourinary tract, as well as virtually every other tissue and organ in the body.
These tubercle bacilli (a common synonym for MTB) are transmitted from one of three sources: humans, cattle (adjective: bovine, hence the species name M. bovis), or birds (adjective: avian), although bovine and avian transmission are much less common than human transmission. Tubercle bacilli are conveyed in droplets expelled by infected people or animals during coughing or sneezing and then inhaled by the new host. After these infectious droplets are inhaled, the infection spreads to the susceptible organ sites by means of the blood and lymphatic system. MTB is a very slow-growing organism, which makes it more difficult to treat than most other bacterial infections. Many of the antibiotics used to treat TB work by inhibiting growth (bacteriostatic) rather than by directly killing the organism. The reason why microorganisms that grow slowly are more difficult to kill is because their cells are not as metabolically active as those of faster-growing organisms. Most bactericidal (cell-killing) drugs work by disrupting critical cellular metabolic processes in the organism. Therefore, the most drug-susceptible organisms are those with faster (not slower) metabolic activity.
The first infectious episode is considered the primary TB infection; reinfection represents the more chronic form of the disease. However, TB does not develop in all people who are exposed to the bacteria. In some cases, the bacteria become dormant and walled off by calcified or fibrous tissues. These patients may test positive for exposure but are not necessarily infectious because of this dormancy process. In immunocompromised patients, TB can inflict devastating and irreversible damage. The steps for diagnosis of TB are listed in Box 41-1.
TB cases have been reported on a national level in the United States beginning in 1953. Since that time, the TB incidence decreased in most years until about 1985. At that point, the epidemic of human immunodeficiency virus (HIV) infection was growing strongly, and the TB incidence began to rise for the first time in 20 years because of the development of TB in patients co-infected with HIV. Many cities were unprepared to handle this reemergence of TB. After an 18% increase in TB incidence between 1985 and 1991, a 50% decline was recorded from 1992 through 2002, and a 3.1% decline was seen from 2009 to 2010. In 2010, 11,182 new cases were reported in the United States. The rate in 2010 represented the lowest recorded number of cases since 1953. This is attributed to intensified public health efforts aimed at preventing, diagnosing, and treating TB as well as HIV infection, including more effective antiretroviral drug therapy (see Chapter 40). However, the rate of decline has now slowed, primarily due to one contributing factor: the number of multidrug-resistant tuberculosis (MDR-TB) cases. An upward trend in drug resistance, especially to isoniazid (abbreviated INH) and rifampin, has been observed since the 1970s. In the 1990s, one third of TB cases in New York City were resistant to at least one drug, and 20% to both isoniazid and rifampin. Fortunately, these numbers have since declined, which has been attributed to stronger TB-related public health efforts.
The prevalence and growth of TB continues to be greater in the larger global community, and TB infects one third of the world’s population. It is currently second only to HIV infection in the number of deaths caused by a single infectious organism. MDR-TB is defined as TB that is resistant to both isoniazid and rifampin, according to the World Health Organization. Close contacts of patients with MDR-TB need to be treated as well. Extensively drug-resistant tuberculosis (XDR-TB) is a relatively rare type of MDR-TB. It is resistant to almost all drugs used to treat TB, including the two best first-line drugs, isoniazid and rifampin, as well as to the best second-line medications. Because XDR-TB is resistant to the most powerful first-line and second-line drugs, patients are left with treatment options that are much less effective and often have worse treatment outcomes. XDR-TB is of special concern for patients who have AIDS or are otherwise immunocompromised. Not only are these patients more likely to contract TB, they are also more likely to die of it. At this point, XDR-TB is rare.
Several factors have contributed to this health care crisis, but one very important source of the problem is the increasing numbers of people in groups that are particularly susceptible to the infection—the homeless, undernourished or malnourished individuals, HIV-infected persons, drug abusers, cancer patients, those taking immunosuppressant drugs, and those who live in crowded and poorly sanitized housing facilities. All of these circumstances also favor the acquisition of a drug-resistant infection. Members of racial and ethnic minority groups are at greater risk than white populations and account for two thirds of new cases. Asian and Hispanic immigrants are at particularly high risk, accounting for more than half of all U.S. cases of foreign-acquired TB.
Pharmacology Overview
Antitubercular Drugs
The drugs used to treat infections caused by all forms of Mycobacterium are called antitubercular drugs, and these drugs fall into two categories: primary or first-line drugs and secondary or second-line drugs. As these designations imply, primary drugs are those tried first, whereas secondary drugs are reserved for more complicated cases, such as those resistant to primary drugs. The antimycobacterial activity, efficacy, and potential adverse and toxic effects of the various drugs determine the class to which they belong. Isoniazid is a primary antitubercular drug and is the most widely used. It can be administered either as the sole drug in the prophylaxis of TB or in combination with other antitubercular drugs in the treatment of TB. The various first-line and second-line antibiotic drugs are listed in Box 41-2. There are also two miscellaneous TB-related injections—one diagnostic, the other a vaccine. These are described in Box 41-3.
An important consideration during drug selection is the likelihood of drug-resistant organisms and drug toxicity. Following are other key elements that are important in the planning and implementation of effective therapy:
Mechanism of Action and Drug Effects
The mechanisms of action of the various antitubercular drugs vary depending on the drug. These drugs act on MTB by inhibiting protein synthesis, inhibiting cell wall synthesis, or various other mechanisms. The antitubercular drugs are listed in Table 41-1 by their mechanism of action. The major effects of drug therapy include reduction of cough and, therefore, reduction of the infectiousness of the patient. This normally occurs within 2 weeks of the initiation of drug therapy, assuming that the patient’s TB strain is drug sensitive.
TABLE 41-1
ANTITUBERCULAR DRUGS: MECHANISMS OF ACTION
| DRUGS | DESCRIPTION |
| Inhibit Protein Synthesis | |
| kanamycin, capreomycin, rifabutin, rifampin, streptomycin | Streptomycin and kanamycin work by interfering with normal protein synthesis and causing the production of faulty proteins. Rifampin and capreomycin act at different points in the protein synthesis pathway than streptomycin and kanamycin. Rifampin inhibits RNA synthesis and may also inhibit DNA synthesis. Human cells are not as sensitive as the mycobacterial cells and are not affected by rifampin except at high drug concentrations. Capreomycin inhibits protein synthesis by preventing translocation on ribosomes. |
| Inhibit Cell Wall Synthesis | |
| cycloserine, ethionamide, isoniazid | Cycloserine acts by inhibiting the amino acid (D-alanine) involved in the synthesis of cell walls. Isoniazid and ethionamide also act at least partly to inhibit the synthesis of wall components, but the mechanisms of these two drugs are still not clearly understood. |
| Other Mechanisms | |
| ethambutol, ethionamide, isoniazid, para-aminosalicylic acid, pyrazinamide | Isoniazid is taken up by mycobacterial cells and undergoes hydrolysis to isonicotinic acid, which reacts with cofactor NAD to form a defective NAD that is no longer active as a coenzyme for certain life-sustaining reactions in the Mycobacterium tuberculosis organism. Ethionamide directly inhibits mycolic acid synthesis, which eventually has the same deleterious effects on the TB organism as isoniazid. Ethambutol affects lipid synthesis, which results in the inhibition of mycolic acid incorporation into the cell wall and thus inhibits protein synthesis. Para-aminosalicylic acid acts as a competitive inhibitor of para-aminobenzoic acid in the synthesis of folate. The mechanism of action of pyrazinamide in the inhibition of TB is unknown. It can be either bacteriostatic or bactericidal, depending on the susceptibility of the particular Mycobacterium organism and the concentration of the drug attained at the site of infection. |
Indications
Antitubercular medications are indicated for the treatment of TB infections, including both pulmonary and extrapulmonary TB. Most antitubercular drugs have not been fully tested for their effects in pregnant women. However, the combination of isoniazid and ethambutol has been used to treat pregnant women with clinically apparent TB without teratogenic complications. Rifampin is another drug that is usually safe during pregnancy and is a more likely choice for more advanced disease.
Besides being used for the initial treatment of TB, antitubercular drugs have also proved effective in the management of treatment failures and relapses. Infection with species of Mycobacterium other than M. tuberculosis and atypical mycobacterial infections have also been successfully treated with these drugs. Nontuberculous Mycobacteria may also be susceptible to antitubercular drugs. However, in general, antitubercular drugs are not as effective against other species of Mycobacterium as they are against MTB. Some of these other species that may be of particular concern in immunocompromised patients such as AIDS patients are M. avium-intracellulare complex, Mycobacterium flavescens, Mycobacterium marinum, and Mycobacterium kansasii. Additional Mycobacterium infections that may respond to antitubercular drugs are those caused by Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium smegmatis, Mycobacterium xenopi, and Mycobacterium scrofulaceum. Treatment regimens for these non-TB mycobacterial infections often include the macrolide antibiotics clarithromycin or azithromycin (see Chapter 38), either alone or in combination with one or more antitubercular drugs.
In summary, antitubercular drugs are primarily used for the prophylaxis or treatment of TB. The effectiveness of these drugs depends on the type of infection, adequate dosing, sufficient duration of treatment, adherence to the drug regimen, and selection of an effective drug combination. The indications of the different antitubercular drugs are listed in Table 41-2.
TABLE 41-2
ANTITUBERCULAR DRUGS: CLINICAL USES
| DRUG | CLINICAL USES |
| amikacin, kanamycin | Used in combination with other antitubercular drugs in the treatment of clinical TB. Not intended for long-term use. |
| capreomycin | Used with other antitubercular drugs for the treatment of pulmonary TB caused by Mycobacterium tuberculosis after first-line drugs fail, drug resistance appears, or drug toxicity occurs. |
| cycloserine | Used with other antitubercular drugs for treatment of active pulmonary and extrapulmonary TB after failure of first-line drugs. |
| ethambutol | Indicated as a first-line drug for treatment of TB. |
| ethionamide | Used with other antitubercular drugs in treatment of clinical TB after failure of first-line drugs and for treatment of other types of mycobacterial infections. |
| isoniazid | Used alone or in combination with other antitubercular drugs in treatment and prevention of clinical TB. |
| para-aminosalicylic acid | Used in combination with other antitubercular drugs for treatment of pulmonary and extrapulmonary M. tuberculosis infection after failure of first-line drugs. |
| pyrazinamide | Used with other antitubercular drugs in treatment of clinical TB. |
| rifabutin | Used to prevent or delay development of Mycobacterium avium-intracellulare bacteremia and disseminated infections in patients with advanced HIV infection. |
| rifampin | Used with other antitubercular drugs in treatment of clinical TB. |
| Used in treatment of diseases caused by mycobacteria other than M. tuberculosis. | |
| Used for preventive therapy in patients exposed to isoniazid-resistant M. tuberculosis. | |
| Used to eliminate meningococci from the nasopharynx of asymptomatic Neisseria meningitidis carriers when risk for meningococcal meningitis is high. | |
| Used for chemoprophylaxis in contacts of patients with HiB infection. | |
| Used with at least one other antiinfective drug in the treatment of leprosy. | |
| Used in the treatment of endocarditis caused by methicillin-resistant staphylococci, chronic staphylococcal prostatitis, and multiple-antiinfective–resistant pneumococci. | |
| rifapentine | Used with other antitubercular drugs in the treatment of clinical TB. |
| streptomycin | Used in combination with other antitubercular drugs in the treatment of clinical TB and other mycobacterial diseases. |
HiB, Haemophilus influenzae type b; HIV, human immunodeficiency virus; TB, tuberculosis.
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